Over the past decade, our studies of osteoporosis that develops after cardiac transplantation (TX) have resulted in new insights into the natural history, demographic and biochemical features of transplantation osteoporosis. The first year after TX is characterized by rapid bone loss (%5 to 12%) at the spine and hip and a very high fracture incidence (20% to 40%). Most studies show that done density stabilizes or improves during the second, and third post-transplant years. We therefore hypothesized that therapy to prevent bone loss could be limited to the first post-transplant years. We therefor hypothesized that therapy to prevent bone loss could be limited to the first post-transplant year. We have completed recruitment (n=146) to a one-year, double-masked phase III clinical trial evaluating the safety and efficacy of two drugs in the prevention of bone loss during the first 12 months after cardiac transplantation: calcitirol [1,25 dihydroxvitamin D] and the bisphosphonate, alendrona te (ALN). Enrollment was completed in June of 2001 and 12 months of follow-up for all participants will be completed in June of 2002. In addition, we have prospectively monitored enrolled participants to assess the effect of study drug withdrawal on rates of bone loss, and fracture during the second and third post-transplant years. Approximately 50% of subjects begin to experience bone loss (ranging as high as 8% at the spine and 9% at the hip) after study drugs are withdrawn. This observation raises several important therapeutic questions. Most important is whether one year of therapy will suffice to prevent osteoporosis after cardiac TX. It is also important to determine whether ALN and calcitirol differ with regard to maintenance of bone density after withdrawal and to elucidate the mechanisms and predictors of bone loss during the second and third post-transplant years. We hypothesize, given the long half-life of bisphosphonates in bone, that subjects who received ALN during the tr ial will be less likely to sustain bone loss after withdrawal of study drugs than those who received calcitirol. Funding for the trial ends in March, 2002. We are now applying for 3 years of support to complete 12 months of observation on those subjects enrolled after March, 2001 and to complete an additional 24 months of follow-up on enrolled participants.